1-216365031-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_206933.4(USH2A):c.706C>A(p.Pro236Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P236H) has been classified as Uncertain significance.
Frequency
Consequence
NM_206933.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.706C>A | p.Pro236Thr | missense_variant | Exon 4 of 72 | 1 | NM_206933.4 | ENSP00000305941.3 | ||
USH2A | ENST00000366942.3 | c.706C>A | p.Pro236Thr | missense_variant | Exon 4 of 21 | 1 | ENSP00000355909.3 | |||
USH2A | ENST00000674083.1 | c.706C>A | p.Pro236Thr | missense_variant | Exon 4 of 73 | ENSP00000501296.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152126Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250978Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135636
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461430Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727022
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152126Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74308
ClinVar
Submissions by phenotype
Usher syndrome type 2A Uncertain:2
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not specified Uncertain:1
Variant classified as Uncertain Significance - Favor Benign. The p.Pro236Thr var iant in USH2A has not been previously reported in individuals with hearing loss, but has been identified in 1/66638 European chromosomes by the Exome Aggregatio n Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs762558966). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. The proline (Pro) at position 236 is not conserved in mammals or evolutionary distant species, raising the possibility th at a change at this position may be tolerated. Additional computational predicti on tools suggest that the p.Pro236Thr variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary , while the clinical significance of the p.Pro236Thr variant is uncertain, the a vailable data suggest that it is more likely to be benign. -
not provided Uncertain:1
This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 236 of the USH2A protein (p.Pro236Thr). This variant is present in population databases (rs762558966, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with USH2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 229626). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt USH2A protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Retinitis pigmentosa 39 Uncertain:1
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Retinal dystrophy Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at